小柯机器人

美国美国西奈山伊坎医学院Amir Horowitz和Nina Bhardwaj共同合作近期取得重要工作进展，他们研究发现NKG2A和HLA-E在膀胱癌中定义了一个可替代的免疫检查点。相关研究工作2022年9月12日在线发表于《癌细胞》杂志上。

研究人员发现，在具有高丰度CD8⁺ T细胞的膀胱肿瘤中，NKG2A与提高生存率和对PD-L1阻断免疫治疗的反应性相关。在膀胱肿瘤中，NKG2A在CD8⁺ T 细胞上的获得时间晚于 PD-1 以及其他完善的免疫检查点。NKG2A⁺ PD-1⁺ CD8⁺ T 细胞通过使用不依赖于T细胞受体（TCR）的先天样机制，对人类白细胞抗原（HLA）I类缺陷型肿瘤作出反应的能力与经典定义的衰竭T细胞不同。随着疾病的进展，膀胱肿瘤的HLA-ABC表达逐渐减少，从而确定了靶向TCR独立的抗肿瘤功能的重要性。

值得注意的是，当肿瘤表达HLA-E时，NKG2A⁺ CD8⁺ T细胞受到抑制，并在NKG2A阻断后以HLA-E依赖性方式部分恢复。总体而言，他们的研究为随后将NKG2A阻断与其他T细胞靶向免疫疗法相结合的临床试验提供了一个框架，在这些临床试验中，肿瘤表达更高水平的HLA-E。

据介绍，程序性细胞死亡蛋白1（PD-1）/程序性死亡配体1（PD-L1）阻断免疫疗法在治疗膀胱癌方面的疗效有限。

附：英文原文

Title: NKG2A and HLA-E define an alternative immune checkpoint axis in bladder cancer

Author: Bérengère Salomé, John P. Sfakianos, Daniel Ranti, Jorge Daza, Christine Bieber, Andrew Charap, Christian Hammer, Romain Banchereau, Adam M. Farkas, Dan Fu Ruan, Sudeh Izadmehr, Daniel Geanon, Geoffrey Kelly, Ronaldo M. de Real, Brian Lee, Kristin G. Beaumont, Sanjana Shroff, Yuanshuo A. Wang, Ying-chih Wang, Tin Htwe Thin, Monica Garcia-Barros, Everardo Hegewisch-Solloa, Emily M. Mace, Li Wang, Timothy O’Donnell, Diego Chowell, Ruben Fernandez-Rodriguez, Mihaela Skobe, Nicole Taylor, Seunghee Kim-Schulze, Robert P. Sebra, Doug Palmer, Eleanor Clancy-Thompson, Scott Hammond, Alice O. Kamphorst, Karl-Johan Malmberg, Emanuela Marcenaro, Pedro Romero, Rachel Brody, Mathias Viard, Yuko Yuki, Maureen Martin, Mary Carrington, Reza Mehrazin, Peter Wiklund, Ira Mellman, Sanjeev Mariathasan, Jun Zhu, Matthew D. Galsky, Nina Bhardwaj, Amir Horowitz

Issue&Volume: 2022/09/12

Abstract: Programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1)-blockadeimmunotherapies have limited efficacy in the treatment of bladder cancer. Here, weshow that NKG2A associates with improved survival and responsiveness to PD-L1 blockadeimmunotherapy in bladder tumors that have high abundance of CD8+ T cells. In bladder tumors, NKG2A is acquired on CD8+ T cells later than PD-1 as well as other well-established immune checkpoints. NKG2A+ PD-1+ CD8+ T cells diverge from classically defined exhausted T cells through their abilityto react to human leukocyte antigen (HLA) class I-deficient tumors using T cell receptor(TCR)-independent innate-like mechanisms. HLA-ABC expression by bladder tumors isprogressively diminished as disease progresses, framing the importance of targetingTCR-independent anti-tumor functions. Notably, NKG2A+ CD8+ T cells are inhibited when HLA-E is expressed by tumors and partly restored uponNKG2A blockade in an HLA-E-dependent manner. Overall, our study provides a frameworkfor subsequent clinical trials combining NKG2A blockade with other T cell-targetedimmunotherapies, where tumors express higher levels of HLA-E.

DOI: 10.1016/j.ccell.2022.08.005

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(22)00369-5

Cancer Cell：《癌细胞》，创刊于2002年。隶属于细胞出版社，最新IF：38.585
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